There are currently no well-established methods to identify and evaluate the mechanisms underlying diabetic macular edema (DME) pathobiology, one of the leading causes of blindness among working-age Americans. As such, the development of pathophysiology-specific therapeutic agents for DME is limited, and the selection of therapies personalized for individual patients remains subjective. Our long-term goal is to develop automated methods that exploit retinal imaging technologies to stratify DME patients into subgroups that reflect specific pathophysiological mechanisms. In turn, we expect that subgrouping according to these mechanisms will facilitate an optimal choice of personalized therapy for each patient. The current paradigm isolates three different pathophysiologic mechanisms, independently or together, as contributing factors to DME: a) capillary endothelial cell dysfunction, b) retinal glial cellular pump dysfunction, and c) retinal pigment epithelium cel pump dysfunction. We propose two interrelated hypotheses based on this paradigm: 1) Fluorescein angiography (FA) and SD-OCT can be quantitatively analyzed using automated algorithms to infer the specific disease mechanism. On FA, the diffuse to focal leakage area (D/F) ratio will reflect the relative predominance of the two pump dysfunction DME subtypes versus the capillary leakage subtype. On SD-OCT, macular thickening and other morphological features indicative of diffuse and focal DME can be identified through layer segmentation. 2) Image analysis using both the D/F ratio and quantitative analysis of SD-OCT will serve as predictive biomarkers for therapeutic responses. More specifically, the FA and SD-OCT markers of diffuse DME will respond better to pharmacotherapy, whereas the markers of focal DME will respond better to focal laser. We will test these hypotheses by pursuit of the following three specific aims: Aim I: Develop automated software to quantify DME subtype imaging biomarkers on FA and SD-OCT. Aim II: Use archived DME cases to refine and validate the automated algorithms developed in Aim I. Aim III: Perform a pilot trial to determine the efficacy of the D/F ratio in predicting anti-VEGF responsiveness in a treatment nave and unbiased population. This project is significant because there is an unmet need for therapies personalized to disease subtype. This project will provide objective DME subtyping methods based on FA and SD-OCT and inferential support for different DME mechanisms. This project is innovative and impactful in terms of new technology and new knowledge. We will utilize novel mathematical concepts and develop algorithms to reliably measure DME imaging biomarkers in an automated fashion in a clinical setting. Developed software will be freely distributed to the public and are expected to become the standard methodology used by clinicians to personalize the choice of therapy or by image reading centers to stratify patients for clinical trials of new DME drugs. Finally, we expect that our novel image processing algorithms and their underlying mathematical frameworks will have an immediate impact on a wide spectrum of medical image processing research applications.